Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming With Cardiosphere-Derived Extracellular Membrane Vesicles

• Published in: Journal of the American College of Cardiology 2015-08, Vol.66 (6), p.599-611
• Main Authors: Tseliou, Eleni, MD, Fouad, Joseph, Reich, Heidi, MD, Slipczuk, Leandro, MD, de Couto, Geoffrey, PhD, Aminzadeh, Mark, MD, Middleton, Ryan, MS, Valle, Jackelyn, BS, Weixin, Liu, MS, Marbán, Eduardo, MD, PhD
• Format: Article
• Language: English
• Subjects: Albumins - physiology; Albumins - therapeutic use; Angiogenesis; Animals; Apoptosis - physiology; Biological activity; cardiac repair; Cardiology; Cardiomyocytes; Cardiovascular; Cell Membrane - physiology; Cell Membrane - transplantation; Cells, Cultured; Clathrin-Coated Vesicles - physiology; Clathrin-Coated Vesicles - transplantation; conversion; exosome; Experiments; Female; Fibroblasts; Fibroblasts - physiology; Fibroblasts - transplantation; Fibrosis - pathology; Fibrosis - therapy; Flow cytometry; growth factor; Humans; Immunology; Internal Medicine; Male; Methods; Myocardial Infarction - pathology; Myocardial Infarction - therapy; Neovascularization, Physiologic - physiology; Ostomy; Polyesters - therapeutic use; Proteins; Rats; Rats, Inbred BN; Rats, Inbred WKY; Rats, Sprague-Dawley; Statistical analysis; Vascular endothelial growth factor
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2015.05.068

Abstract Background Cardiosphere-derived cells mediate therapeutic regeneration in patients after myocardial infarction and are undergoing further clinical testing for cardiomyopathy. The beneficial effects of cardiosphere-derived cells are mediated by the secretion of exosomes and possibly other extracellular membrane vesicles (EMVs). Objectives This study sought to investigate the effect of cardiosphere-derived EMVs (CSp-EMVs) on fibroblasts in vitro and tested whether priming with CSp-EMVs could confer salutary properties on fibroblasts in vivo. Methods CSp-EMVs were isolated from serum-free media conditioned for 3 days by cardiospheres. Dermal fibroblasts were primed with CSp-EMVs for 24 h followed by exosomal micro-ribonucleic acid profiling. In vivo, we injected CSp-EMV−primed or −unprimed dermal fibroblasts (or CSp-EMVs) in a chronic rat model of myocardial infarction and defined the functional and structural consequences. Results CSp-EMVs amplified their own biological signals: exposure of “inert” fibroblasts to CSp-EMVs rendered the fibroblasts therapeutic. Intramyocardially injected CSp-EMV−primed (but not unprimed) fibroblasts increased global pump function and vessel density while reducing scar mass. CSp-EMV priming caused fibroblasts to secrete much higher levels of stromal-cell-derived factor 1 and vascular endothelial growth factor and dramatically changed the micro-ribonucleic acid profile of fibroblast-secreted EMVs in vitro. The priming was followed by significant angiogenic and cardioprotective effects. Conclusions CSp-EMVs alter fibroblast phenotype and secretome in a salutary positive-feedback loop. The phenotypic conversion of inert cells to therapeutically active cells reveals a novel mechanism for amplification of exosome bioactivity.